Detailed structural characterization of unbound protein phosphatase 1 inhibitors.
Protein phosphatase 1 (PP1) is an essential and ubiquitous serine/threonine protein phosphatase that is regulated by more than 100 known inhibitor and targeting proteins. It is currently unclear how protein inhibitors distinctly and specifically regulate PP1 to enable rapid responses to cellular alterations. We demonstrate that two PP1 inhibitors, I-2 and DARPP-32, belong to the class of intrinsically unstructured proteins (IUPs). We show that both inhibitors have distinct preferences for transient local and long-range structure. These preferences are likely their structural signature for their interaction with PP1. Furthermore, we show that upon phosphorylation of Thr(34) in DARPP-32, which turns DARPP-32 into a potent inhibitor of PP1, neither local nor long-range structure of DARPP-32 is altered. Therefore, our data suggest a role for these transient three-dimensional topologies in binding mechanisms that enable extensive contacts with PP1's invariant surfaces. Together, these interactions enable potent and selective inhibition of PP1.
Dancheck
Barbara
B
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
Nairn
Angus C
AC
Peti
Wolfgang
W
D000595:Amino Acid Sequence; D000818:Animals; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017433:Protein Structure, Secondary; D051381:Rats; D013379:Substrate Specificity
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D054645:Protein Phosphatase 1